Heme and hemoglobin suppress amyloid β–mediated inflammatory activation of mouse astrocytes

Sitara B. Sankar, Rebecca K. Donegan, Kajol J. Shah, Amit R. Reddi, Levi B. Wood
2018 Journal of Biological Chemistry  
Glial immune activity is a key feature of Alzheimer's disease (AD). Given that the blood factors heme and hemoglobin (Hb) are both elevated in AD tissues and have immunomodulatory roles, here we sought to interrogate their roles in modulating amyloid β (Aβ)-mediated inflammatory activation of astrocytes. We discovered that heme and Hb suppress immune activity of primary mouse astrocytes by reducing expression of several proinflammatory cytokines (e.g. RANTES) and the scavenger receptor CD36,
more » ... reducing internalization of Aβ 1-42 by astrocytes. Moreover, we found that certain soluble (> 75 kDa) Aβ 1-42 oligomers are primarily responsible for astrocyte activation and that heme or Hb association with these oligomers reverses inflammation. We further found that heme up-regulates phospho-protein signaling in the phosphoinositide 3-kinase (PI3K)/Akt pathway, which regulates a number of immune functions, including cytokine expression and phagocytosis. The findings in this work suggest that dysregulation of Hb and heme levels in AD brains may contribute to impaired amyloid clearance and that targeting heme homeostasis may reduce amyloid pathogenesis. Altogether, we propose heme as a critical molecular link between amyloid pathology and AD risk factors, such as aging, brain injury, and stroke, which increase Hb and heme levels in the brain. http://www.jbc.org/cgi/
doi:10.1074/jbc.ra117.001050 pmid:29871926 fatcat:whq5zd4rzzbr5jupe55omghi7q